ArticleThe Journal of biological chemistry2012
Structural and kinetic evidence that catalytic reaction of human UDP-glucose 6-dehydrogenase involves covalent thiohemiacetal and thioester enzyme intermediates.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- Dehydrogenase WRD1 regulates plant growth by modulating cell wall formation, ROS homeostasis, and auxin signaling in rice.The Plant journal : for cell and molecular biology · 2026Article
- Phosphorylation of UDP-glucose dehydrogenase increases glycosaminoglycan biosynthesis and promotes tumor cell motility, spheroid growth, and therapeutic resistance.Matrix biology : journal of the International Society for Matrix Biology · 2025Article
- Recent insights into the implications of UGDH mutations for human developmental disease.Biochemical Society transactions · 2025Review
- Computational Study of Base-Catalyzed Thiohemiacetal Decomposition inThe journal of physical chemistry. B · 2023Article
- UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis.Nature communications · 2023Article
- New Role of Water in Transketolase Catalysis.International journal of molecular sciences · 2023Article
- Mechanisms of coordinating hyaluronan and glycosaminoglycan production by nucleotide sugars.American journal of physiology. Cell physiology · 2022Review
- Article
- Functional and Structural Characterization of the UDP-Glucose Dehydrogenase Involved in Capsular Polysaccharide Biosynthesis fromBiochemistry · 2021Article
- Integration of Sugar Metabolism and Proteoglycan Synthesis by UDP-glucose Dehydrogenase.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2021Review
- Multi-Omics Approach Reveals the Potential Core Vaccine Targets for the Emerging Foodborne PathogenFrontiers in microbiology · 2021Article
- Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.Nature communications · 2020Article
- Human Glycerol 3-Phosphate Dehydrogenase: X-ray Crystal Structures That Guide the Interpretation of Mutagenesis Studies.Biochemistry · 2019Article
- UDP-glucose Dehydrogenase: The First-step Oxidation Is an NADInternational journal of biological sciences · 2019Article
- Analysis of Posttranslational Activation of Alternative Oxidase Isoforms.Plant physiology · 2017Article
- Structural Characterization of CalS8, a TDP-α-D-Glucose Dehydrogenase Involved in Calicheamicin Aminodideoxypentose Biosynthesis.The Journal of biological chemistry · 2015Article
- Defined PEG smears as an alternative approach to enhance the search for crystallization conditions and crystal-quality improvement in reduced screens.Acta crystallographica. Section D, Biological crystallography · 2015Article
- UDP-glucose dehydrogenase activity and optimal downstream cellular function require dynamic reorganization at the dimer-dimer subunit interfaces.The Journal of biological chemistry · 2013Article
- Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- UDP-glucose dehydrogenase polymorphisms from patients with congenital heart valve defects disrupt enzyme stability and quaternary assembly.The Journal of biological chemistry · 2012Article
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
Biosynthesis of UDP-glucuronic acid by UDP-glucose 6-dehydrogenase (UGDH) occurs through the four-electron oxidation of the UDP-glucose C6 primary alcohol in two NAD(+)-dependent steps. The catalytic reaction of UGDH is thought to involve a Cys nucleophile that promotes formation of a thiohemiacetal enzyme intermediate in the course of the first oxidation step. The thiohemiacetal undergoes further oxidation into a thioester, and hydrolysis of the thioester completes the catalytic cycle. Herein we present crystallographic and kinetic evidence for the human form of UGDH that clarifies participation of covalent catalysis in the enzymatic mechanism. Substitution of the putative catalytic base for water attack on the thioester (Glu(161)) by an incompetent analog (Gln(161)) gave a UGDH variant (E161Q) in which the hydrolysis step had become completely rate-limiting so that a thioester enzyme intermediate accumulated at steady state. By crystallizing E161Q in the presence of 5 mm UDP-glucose and 2 mm NAD(+), we succeeded in trapping a thiohemiacetal enzyme intermediate and determined its structure at 2.3 Å resolution. Cys(276) was covalently modified in the structure, establishing its role as catalytic nucleophile of the reaction. The thiohemiacetal reactive C6 was in a position suitable to become further oxidized by hydride transfer to NAD(+). The proposed catalytic mechanism of human UGDH involves Lys(220) as general base for UDP-glucose alcohol oxidation and for oxyanion stabilization during formation and breakdown of the thiohemiacetal and thioester enzyme intermediates. Water coordinated to Asp(280) deprotonates Cys(276) to function as an aldehyde trap and also provides oxyanion stabilization. Glu(161) is the Brønsted base catalytically promoting the thioester hydrolysis.
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